Bis-thiadiazole derivatives or salts thereof and agrohorticultural disease controller and method for using the same

ABSTRACT

A bis-thiadiazole derivative represented by general formula (I):                    
     wherein R 1  and R 2  represent H, C 1 -C 8  alkyl, halo C 1 -C 4  alkyl, unsubstituted or substituted phenyl, 5- or 6-membered heterocycle containing 1 to 3 hetero atoms selected from O, S and N, or the like; X 1  and X 2  represent O or S; Y 1  and Y 2  represent O, S or —N(R 3 )—; R represents C 0 -C 30  alkylene. —(C) a (R 3 )(R 4 )— (R 3  and R 4  represent H, halogen, OH, C 1 -C 4  alkyl, halo C 1 -C 4  alkyl or the like) or the like; and a is 0 to 30; or a salt thereof, and an agrohorticultural disease controller containing said derivative or salt as an active ingredient.

This is a Continuation International Appln. No. PCT/JP97/03468 filed Sep. 29, 1997 which designated the U.S.

TECHNICAL FIELD

The present invention relates to bis-thiadiazole derivatives or salts thereof and an agrohorticultural disease controller containing said compounds as an active ingredient.

BACKGROUND ART

1,2,3-Thiadiazoles derivatives are disclosed in JP-A-2-149579/1990 as an agent for treating central nervous system diseases, in JP-A-54-9272/1979, JP-A-3-181463/1991, JA-A-4-234881/1992, Canadian Patent 947297, etc. as a herbicide and a plant growth regulator, and in WO 9501340 and JP-A-7-252242/1995 as a fungicide.

DISCLOSURE OF THE INVENTION

With the aim of creating a novel agrohorticultural disease controller, the present inventors have conducted extensive studies to find that the bis-thiadiazole derivatives of the present invention or salts thereof are useful as an agrohorticultural disease controller. Based on this finding, the present invention has been accomplished.

The present invention relates to bis-thiazole derivatives represented by the following general formula (I) or salts thereof, and an agrohorticultural disease controller containing said bis-thiadiazole derivative or a salt thereof as an active ingredient, and a method for using said disease controller:

wherein R¹ and R², same or different, represent hydrogen atom, C₁-C₈ alkyl group, halo C₁-C₄ alkyl group, phenyl group, substituted phenyl group having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, 5- or 6-membered hererocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, or substituted 5- or 6-membered heterocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom and having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups;

X¹ and X², same or different, represent oxygen atom or sulfur atom;

Y¹ and Y², same or different, represent oxygen atom, sulfur atom or

—N(R³)— in which R³ is as defined later; and

R represents C₀-C₃₀ alkylene group, an alkylene group of the following formula:

in which R³ and R⁴, same or different, represent hydrogen atom, halogen atom, hydroxyl group, nitro group, cyano group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, C₁-C₄ alkylsulfinyl group, C₁-C₄ alkylsulfonyl group, hydroxy C₁-C₄ alkyl group, C₁-C₄ alkoxy C₁-C₄ alkyl group, C₁-C₄ alkoxycarbonyl group, amino group, substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl group, phenyl group and substituted phenyl groups having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, amino C₁-C₄ alkyl group, substituted amino C₁-C₄ alkyl group having 1 or 2 same or different substituents selected from C₁-C₄ alkyl group and substituted phenyl groups having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, phenyl group, substituted phenyl group having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, phenyl C₁-C₄ alkyl group, substituted phenyl C₁-C₄ alkyl group having, on the ring thereof, 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, phenoxy group, substituted phenoxy group having, on the ring thereof, 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, phenoxy C₁-C₄ alkyl group, substituted phenoxy C₁-C₄ alkyl group having, on the ring thereof, 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, 5- or 6-membered heterocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, substituted 5- or 6-membered heterocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom and having 1 to 4 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, 5- or 6-membered heterocycle C₁-C₄ alkyl group containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, substituted 5- or 6-membered hetero cycle C₁-C₄ alkyl group containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom and having 1 to 4 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, or a group

(wherein R⁶ represents C₁-C₆ alkylene group, substituted C₁-C₆ alkylene group substituted by one or more same or different halogen atoms or C₁-C₄ alkyl groups, or C₁-C₆ alkylene group which may be intercepted by

—O—,

—S(O)_(n)—

in which n is an integer of 0-2, or

—N(R⁸)—

in which R⁸ represents hydrogen atom, halogen atom, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxycarbonyl group, phenyl group, substituted phenyl group having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, phenyl C₁-C₄ alkyl group, substituted phenyl C₁-C₄ alkyl group having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, or

(wherein R¹¹ represents C₁-C₆ alkylene group or substituted C₁-C₆ alkylene group having one or more substituents selected from the group consisting of halogen atom and C₁-C₄ alkyl group;

R¹² represents hydrogen atom, C₁-C₈ alkyl group, halo C₁-C₄ alkyl group, phenyl group, substituted phenyl group having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, 5- or 6-membered heterocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, or substituted 5- or 6-membered heterocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom and having 1 to 4 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups;

Y⁴ represents

—O—,

—S— or

—N(R¹³)— in which R¹³ represents hydrogen atom or C₁-C₄ alkyl group;

X⁴ represents oxygen atom or sulfur atom;

q represents an integer of 0 to 1; and

r represents an integer of 0 to 1);

R⁷ represents hydrogen atom, C₁-C₈ alkyl group, halo C₁-C₈ alkyl group, phenyl group, substituted phenyl group having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, phenyl C₁-C₄ alkyl group, substituted phenyl C₁-C₄ alkyl group having, on the ring thereof, 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, 5- or 6-membered heterocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, or substituted 5- or 6-membered heterocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom and having, on the ring thereof, 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups;

Y³ represents

—O—,

—S— or

—N(R⁸)— in which R⁸ is as defined above;

X³ represents oxygen atom or sulfur atom;

m represents an integer of 0 to 5; and

p represents an integer of 0 or 1); and

letter a represents an integer of 0 to 30;

further, R³ and R⁴ may be taken conjointly to form a 3- to 8-membered ring including a C₀-C₇ alkylene group, and said 3- to 8-membered ring may be intercepted by

—O—,

—S(O)_(n)— in which n represents an integer of 0-2,

—N(R⁸)— in which R⁸ is as defined above, or

—C(R⁹)(R¹⁰)— in which R⁹ and R¹⁰, same or different, represent halogen atom, C₁-C₄ alkyl group or a group of the following formula:

in which R¹¹, R¹², X⁴, Y⁴, q and r are as defined above; and R⁹ and R¹⁰ may be taken conjointly to form a 3- to 7-membered ring including a C₂-C₆ alkylene group; and

R alternatively represents C₀-C₃₀ alkylene group which may be intercepted by one or more same or different group selected from the group consisting of

—O—,

—S(O)_(n)— in which n is as defined above,

—N(R³)— in which R³ is as defined above,

—C(R³)═C(R⁴)— in which R³ and R⁴ are as defined above,

—C≡C—,

(Z represents halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group, substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, or a group of the following formula:

in which R⁶, R⁷, Y³, X³, m and p are as defined above) and

(Z is as defined above).

BEST MODE FOR CARRYING OUT THE INVENTION

In the definitions of the substituents in the bis-thiadiazole derivatives of the present invention represented by general formula (I), the term “halogen atom” means chlorine atom, bromine atom, iodine atom or fluorine atom; the term “C₁-C₈ alkyl group” means a straight or branched chain alkyl group having 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like; the term “halo C₁-C₄ alkyl group” means an same or different straight or branched chain alkyl group substituted by at least one halogen atom; and the term “5- or 6-membered heterocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom” means a 5- or 6-membered heterocycle such as furan, thiophene, pyrrole, oxazole, thiazole, isothiazole, pyrazole, imidazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,4-triazole, pyridine, pyridazine, pyrimidine, pyrazine, pyrrolidine, piperidine, morpholine, thiomorpholine, dithiolane, dithiane, piperazine, dioxalane, imidazolidine and the like.

As examples of the salt of the bis-thiadiazole derivative represented by general formula (I), there can be referred to salts of alkali metals such as sodium, potassium and the like, salts of alkaline earth metals such as calcium, magnesium and the like, ammonium salts, substituted ammonium salts substituted by one or more same or different substituents selected from the group consisting of C₁-C₁₂ alkyl group, phenyl group, substituted phenyl group, benzyl group and substituted benzyl group, guanidium salt and the like.

As preferred substituents in the general formula (I) of the present invention, the following can be referred to. Thus, as R¹ and R² which may be same or different, methyl group, ethyl group, i-propyl group, cyclopropyl group and the like are preferred. As X¹ and X², oxygen atom is preferred. As Y¹ and Y², oxygen atom and —NH— are preferred. As R, preferred are phenylene group, alkylene group having 2-6 carbon atoms, —(CH₂CH₂O)₁₋₃— and a group of the following formula:

The bis-thiadiazole derivatives of the present invention represented by formula (I) or salts thereof can be produced, for example, by the following production processes.

PRODUCTION PROCESS 1

wherein R, R¹, R², Y¹ and Y² are as defined above and Hal represents halogen atom.

A bis-thiadiazole derivative represented by general formula (I) can be produced by reacting a compound represented by general formula (II) with a compound represented by general formula (IV) in the absence or presence of a base, in the absence or presence of an inert solvent.

This reaction can be performed according to the method described in “Shin Jikken Kagaku Koza”, Vol. 15 (II), p.1012 (Maruzen K. K.) and ibid. p.1142.

PRODUCTION PROCESS 2

(a case where Y¹ and Y² are oxygen atoms)

wherein R, R¹, R² and Hal are as defined above.

A bis-thiadiazole derivative represented by general formula (I—I) can be produced by reacting a compound represented by general formula (III) with a compound represented by general formula (V) in the presence or absence of a base, in the presence or absence of an inert solvent.

This reaction can be performed according to the description of “Shin Jikken Kagaku Koza”, Vol. 15 (II), p. 1008.

PRODUCTION PROCESS 3

wherein R, R¹, R², Y¹, Y² and Hal are as defined above.

A bis-thiadiazole derivative represented by general formula (I) can be produced by reacting a compound represented by general formula (II) with a compound represented by general formula (IV) in the presence or absence of a base, in the presence or absence of an inert solvent to form a thiadiazole derivative represented by general formula (VI), and after isolating the compound (VI) or without isolating (VI), reacting the compound (VI) with a compound represented by general formula (II′).

This reaction can be performed according to the known method described in the paragraph of Method 1.

The compounds represented by general formulas (II) and (III) which are starting compounds in the Production process 1 and 2 can be produced, for example, by the known method described below.

wherein R¹ and Hal are as defined above, R′ represents C₁-C₈ alkyl group, and R″ represents C₁-C₄ alkyl group, C₁-C₄ alkoxy group or an amino group which may have a substituent.

A compound represented by general formula (II) can be produced by reacting a compound represented by general formula (X) with a compound represented by general formula (IX) to form a compound represented by general formula (VIII) and, after isolating the compound (VIII) or without isolating (VIII), subjecting the compound (VIII) to a ring closure reaction using thionyl chloride to form a compound represented by general formula (VII), and after isolating the compound (VII) or without isolating (VII), hydrolyzing the compound (VII) to form a compound represented by general formula (III), and after isolating the compound (III) or without isolating (III), halogenating the compound (III) with a halogenating agent.

This reaction can be performed according to a known method described in J. Am. Chem. Soc., 77, 5359 (1955), etc.

The compound represented by general formula (II′) can also be produced by the same method as above.

Next, typical examples of the bis-thiadiazole derivative of the present invention represented by general formula (I) will be mentioned below. The present invention is by no means limited by these examples.

In Table 1, meanings of the abbreviations are as follows:

Me: methyl group, Et: ethyl group, Pr: propyl group,

Bu: butyl group, Ph: phenyl or phenylene group,

TABLE 1 No R¹ X¹ Y¹ R R² X² Y² 1 Me O O CH₂ Me O O 2 Me O O (CH₂)₂ Me O O 3 Me O O (CH₂)₃ Me O O 4 Me O O (CH₂)₄ Me O O 5 Me O O (CH₂)₅ Me O O 6 Me O O (CH₂)₆ Me O O 7 Me O O (CH₂)₇ Me O O 8 Me O O (CH₂)₈ Me O O 9 Me O O (CH₂)₉ Me O O 10 Me O O (CH₂)₁₀ Me O O 11 Me O O (CH₂)₁₁ Me O O 12 Me O O (CH₂)₁₂ Me O O 13 Me O O (CH₂)₁₂ Me O O 14 Me O O (CH₂)₁₄ Me O O 15 Me O O (CH₂)₁₅ Me O O 16 Me O O (CH₂)₁₆ Me O O 17 Me O O (CH₂)₁₇ Me O O 18 Me O O (CH₂)₁₈ Me O O 19 Me O O (CH₂)₁₉ Me O O 20 Me O O (CH₂)₂₀ Me O O 21 Me O O CH₂CH(Me) Me O O 22 Me O O CH₂CH(CH₂F) Me O O 23 Me O O CH₂CH(CH₂Cl) Me O O 24 Me O O CH₂CH(CH₂Br) Me O O 25 Me O O CH₂CH(Et) Me O O 26 Me O O CH₂CH(n-Pr) Me O O 27 Me O O CH₂CH(i-Pr) Me O O 28 Me O O CH₂CH(n-Bu) Me O O 29 Me O O CH₂CH(i-Bu) Me O O 30 Me O O CH₂CH(t-Bu) Me O O 31 Me O O CH₂CH(n-C₆H₁₃) Me O O 32 Me O O CH₂CH(n-C₆H₁₇) Me O O 33 Me O O CH₂CH(n-C₁₀H₂₁) Me O O 34 Me O O CH₂CH(n-C₁₂H₂₅) Me O O 35 Me O O CH₂CH(Ph) Me O O 36 Me O O CH₂CH(2-Cl—Ph) Me O O 37 Me O O CH₂CH(3-Cl—Ph) Me O O 38 Me O O CH₂CH(4-Cl—Ph) Me O O 39 Me O O CH₂CH(2-Me—Ph) Me O O 40 Me O O CH₂CH(3-Me—Ph) Me O O 41 Me O O CH₂CH(4-Me—Ph) Me O O 42 Me O O CH₂CH(4-i-Pr—Ph) Me O O 43 Me O O CH₂CH(3-i-PrO—Ph) Me O O 44 Me O O CH₂CH(4-Br—Ph) Me O O 45 Me O O CH₂CH(4-CF₃—Ph) Me O O 46 Me O O CH(Me)CH(Me) Me O O 47 Me O O CH₂C(Me)₂ Me O O 48 Me O O CH(Me)C(Me)₂ Me O O 49 Me O O C(Me)₂C(Me)₂ Me O O 50 Me O O CH₂CH(CH₂OMe) Me O O 51 Me O O CH₂CH(CH₂OPh) Me O O 52 Me O O CH₂CH(CH₂O(3-Cl—Ph)) Me O O 53 Me O O CH₂CH(CH₂O(4-MeO—Ph)) Me O O 54 Me O O CH₂CH(CH₂O—CH₂Ph) Me O O 55 Me O O CH₂CH(CH₂O—COMe) Me O O 56 Me O O CH₂CH(CH₂O—COBu-t) Me O O 57 Me O O CH₂CH(CH₂O—COPh) Me O O 58 Me O O CH₂CH(CH₂O—CO(2-Cl—Ph)) Me O O 59 Me O O CH₂CH(CH₂O—CO(3-Cl—Ph)) Me O O 60 Me O O CH₂CH(CH₂O—CO(4-Cl—Ph)) Me O O 61 Me O O CH₂CH(CH₂O—CO(4-CF₃—Ph)) Me O O 62 Me O O CH₂CH(CH₂SMe) Me O O 63 Me O O CH₂CH(CH₂SOMe) Me O O 64 Me O O CH₂CH(CH₂SO₂Me) Me O O 65 Me O O CH₂CH(CH₂N(Me)₂) Me O O 66 Me O O CH₂CH(CH₂N(Et)₂) Me O O 67 Me O O CH₂CH(CH₂—Q₁) Me O O 68 Me O O CH₂CH(CH₂—Q₂) Me O O 69 Me O O CH₂CH(CH₂NHCOMe) Me O O 70 Me O O CH₂CH(CH₂NHCOEt) Me O O 71 Me O O CH₂CH(CH₂NHCOPr-i) Me O O 72 Me O O CH₂CH(CH₂NHCOBu-n) Me O O 73 Me O O CH₂CH(CH₂NHCOPh) Me O O 74 Me O O CH₂CH(CH₂NHCO(2-Cl—Ph) Me O O 75 Me O O CH₂CH(CH₂NHCO(3-Cl—Ph) Me O O 76 Me O O CH₂CH(CH₂NHCO(4-Cl—Ph) Me O O 77 Me O O CH₂CH(CN) Me O O 78 Me O O CH(Ph)CH(Ph) (meso) Me O O 79 Me O O CH(Ph)CH(Ph) (+/−) Me O O 80 Me O O CH₂CH₂CH(Me) Me O O 81 Me O O CH₂CH(Me)CH₂ Me O O 82 Me O O CH₂C(Me)₂CH₂ Me O O 83 Me O O CH₂C(CH₂Br)₂CH₂ Me O O 84 Me O O CH(Me)CH₂CH(Me) Me O O 85 Me O O CH(Me)CH₂C(Me)₂ Me O O 86 Me O O C(Me)₂CH₂C(Me)₂ Me O O 87 Me O O CH₂C(Me)(Et)CH₂ Me O O 88 Me O O CH₂C(Et)₂CH₂ Me O O 89 Me O O CH₂C(Me)(n-Pr)CH₂ Me O O 90 Me O O CH(i-Pr)C(Me)₂CH₂ Me O O 91 Me O O CH(n-Pr)C(Et)₂CH₂ Me O O 92 Me O O CH₂C(Et)(n-Bu)CH₂ Me O O 93 Me O O CH₂C(Me)(CH₂O—COQ₃)CH₂ Me O O 94 Me O O CH₂C(NO₂)(CH₂O—COQ₃)CH₂ Me O O 95 Me O O CH₂C(Et)(CH₂O—COQ₃)CH₂ Me O O 96 Me O O CH₂C(Et)(CH₂O—COQ₃)CH₂ Me O O 97 Me O O CH₂CH(Cl)CH₂ Me O O 98 Me O O CH₂CH(Br)CH₂ Me O O 99 Me O O CH₂C(Br)(NO₂)CH₂ Me O O 100 Me O O CH₂CH(OH)CH₂ Me O O 101 Me O O CH₂CH(OMe)CH₂ Me O O 102 Me O O CH₂CH(OCH₂Ph)CH₂ Me O O 103 Me O O CH₂CH(O—COMe)CH₂ Me O O 104 Me O O CH₂CH(O—COPh)CH₂ Me O O 105 Me O O CH₂CH(O—CO(4-Cl—Ph))CH₂ Me O O 106 Me O O CH₂CH(O—COQ₃)CH₂ Me O O 107 Me O O CH₂CH(O—COOMe)CH₂ Me O O 108 Me O O CH₂CH(NH₂)CH₂ Me O O 109 Me O O CH₂C(Me)(NHCOQ₃)CH₂ Me O O 110 Me O O CH₂C(Et)(NHCOQ₃)CH₂ Me O O 111 Me O O CH₂C(CH₂COQ₃)(NHCOQ₃)CH₂ Me O O 112 Me O O CH₂CH(NHCOMe)CH₂ Me O O 113 Me O O CH₂CH(NHCOPh)CH₂ Me O O 114 Me O O CH₂CH(NHCOQ₃)CH₂ Me O O 115 Me O O CH₂CH(SMe)CH₂ Me O O 116 Me O O CH₂C(COOMe)₂CH₂ Me O O 117 Me O O CH₂C(COOEt)₂CH₂ Me O O 118 Me O O CH₂C(COOPr-i)₂CH₂ Me O O 119 Me O O CH₂C(CN)₂CH₂ Me O O 120 Me O O CH₂CH₂C(Me)₂ Me O O 121 Me O O CH(Me)CH₂C(Me)₂ Me O O 122 Me O O CH(Me)CH₂CH₂C(Me)₂ Me O O 123 Me O O CH₂CH(Cl)CH(Cl)CH₂ Me O O 124 Me O O CH₂CH(Br)CH(Br)CH₂ Me O O 125 Me O O CH₂CH₂CH(OH)CH₂ Me O O 126 Me O O CH₂CH₂CH(O—COQ₃)CH₂ Me O O 127 Me O O CH₂CH(O—COQ₃)CH(O—COQ₃)CH₂ Me O O 128 Me O O CH₂CH(COOMe)CH(COOMe)CH₂ Me O O 129 Me O O CH₂CH(COOEt)CH(COOEt)CH₂ Me O O 130 Me O O CH₂CH₂CH₂CH(Me) Me O O 131 Me O O CH₂CH₂CH₂CH₂CH(Me) Me O O 132 Me O O (CH₂)₃C(NO₂)((CH₂)₃O—COQ₃)(CH₂)₃ Me O O 133 Me O O CH₂CH═CHCH₂ (E) Me O O 134 Me O O CH₂CH═CHCH₂ (Z) Me O O 135 Me O O CH₂C(Me)═C(Me)CH₂ (E) Me O O 136 Me O O CH₂CH═C(Me)CH₂ (E) Me O O 137 Me O O CH₂CH═C(Me)CH₂ (Z) Me O O 138 Me O O CH₂CH═C(Cl)CH₂ (E) Me O O 139 Me O O CH₂CH═C(Cl)CH₂ (Z) Me O O 140 Me O O CH₂C≡CCH₂ Me O O 141 Me O O 1-cyclo-C₅H₈-2 Me O O 142 Me O O 1-cyclo-C₅H₈-3 Me O O 143 Me O O 1-cyclo-C₆H₁₀-2 Me O O 144 Me O O 1-cyclo-C₆H₁₀-3 Me O O 145 Me O O 1-cyclo-C₆H₁₀-4 Me O O 146 Me O O Q₂₀ Me O O 147 Me O O 1-(5-O-COQ₃-cyclo-C₅H₁₀)-3 Me O O 148 Me O O CH₂-1-cyclo-C₆H₁₀-1 Me O O 149 Me O O CH₂-1-cyclo-C₆H₁₀-2-CH₂ Me O O 150 Me O O Q₂₁ Me O O 151 Me O O Q₂₂ Me O O 152 Me O O 1-cyclo-C₈H₁₄-2 Me O O 153 Me O O Q₂₃ Me O O 154 Me O O 1-Ph-2 Me O O 155 Me O O 1-Ph-3 Me O O 156 Me O O 1-Ph-4 Me O O 157 Me O O 1-(3-F—Ph)-2 Me O O 158 Me O O 1-(3-Me—Ph)-2 Me O O 159 Me O O 1-(3-MeO—Ph)-2 Me O O 160 Me O O 1-(4-Cl—Ph)-3 Me O O 161 Me O O 1-(4,6-Cl₂—Ph)-3 Me O O 162 Me O O 1-(5-Me—Ph)-3 Me O O 163 Me O O 1-(4-Et—Ph)-3 Me O O 164 Me O O 1-(5-C₅H₁₁—Ph)-3 Me O O 165 Me O O 1-(5-OMe—Ph)-3 Me O O 166 Me O O 1-(5-O—COQ₃—Ph)-3 Me O O 167 Me O O 1-(2-Cl—Ph)-4 Me O O 168 Me O O 1-(2-Me—Ph)-4 Me O O 169 Me O O 1-(2,3,5-Me₃—Ph)-4 Me O O 170 Me O O

Me O O 171 Me O O

Me O O 172 Me O O

Me O O 173 Me O O

Me O O 174 Me O O

Me O O 175 Me O O

Me O O 176 Me O O

Me O O 177 Me O O

Me O O 178 Me O O CH(Et)CH(Et) Me O O 179 Me O O

Me O O 180 Me O O

Me O O 181 Me O O

Me O O 182 Me O O

Me O O 183 Me O O

Me O O 184 Me O O

Me O O 185 Me O O

Me O O 186 Me O O

Me O O 187 Me O O CH₂CH₂OCH₂CH₂ Me O O 188 Me O O CH₂CH₂(OCH₂CH₂)₂ Me O O 189 Me O O CH₂CH₂(OCH₂CH₂)₃ Me O O 190 Me O O CH₂CH₂(OCH₂CH₂)₄ Me O O 191 Me O O CH₂CH₂(OCH₂CH₂)₅ Me O O 192 Me O O CH₂CH₂(OCH₂CH₂)₆ Me O O 193 Me O O CH₂CH₂(OCH₂CH₂)₇ Me O O 194 Me O O CH₂CH₂(OCH₂CH₂)₈ Me O O 195 Me O O CH₂CH₂(OCH₂CH₂)₉ Me O O 196 Me O O CH₂CH₂(OCH₂CH₂)_(n) (Mean n = 3) Me O O 197 Me O O CH₂CH₂(OCH₂CH₂)_(n) (Mean n = 7) Me O O 198 Me O O CH₂CH₂(OCH₂CH₂)_(n) (Mean n = 10) Me O O 199 Me O O CH₂CH₂CH₂OCH₂CH₂CH₂ Me O O 200 Me O O CH₂CH₂SCH₂CH₂ Me O O 201 Me O O CH₂CH₂SSCH₂CH₂ Me O O 202 Me O O CH₂CH₂SOCH₂CH₂ Me O O 203 Me O O CH₂CH₂SO₂CH₂CH₂ Me O O 204 Me O O CH_(2CH) ₂CH₂SCH₂CH₂CH₂ Me O O 205 Me O O CH₂CH₂(SCH₂CH₂)₂ Me O O 206 Me O O CH₂CH₂NHCH₂CH₂ Me O O 207 Me O O CH₂CH₂N(Me)CH₂CH₂ Me O O 208 Me O O CH₂CH₂N(Et)CH₂CH₂ Me O O 209 Me O O CH₂CH₂N(Ph)CH₂CH₂ Me O O 210 Me O O CH₂CH₂N(3-Cl—Ph)CH₂CH₂ Me O O 211 Me O O CH₂CH₂N(COMe)CH₂CH₂ Me O O 212 Me O O CH₂CH₂N(COEt)CH₂CH₂ Me O O 213 Me O O CH₂CH₂N(COBu-t)CH₂CH₂ Me O O 214 Me O O CH₂CH₂N(COPh)CH₂CH₂ Me O O 215 Me O O CH₂CH₂N(CO(4-Cl—Ph))CH₂CH₂ Me O O 216 Me O O CH₂CH₂N(COQ₃)CH₂CH₂ Me O O 217 Me O O CH₂CH₂N(COOMe)CH₂CH₂ Me O O 218 Me O O CH(Me)CH₂N(COQ₃)CH₂CH(Me) Me O O 219 Me O O CH₂CH₂N(CH₂CH₂O—COQ₃)CH₂CH₂ Me O O 220 Me O O CH(Me)CH₂N(CH₂CH₂O—COQ₃)CH₂CH₂ Me O O 221 Me O O CH₂CH₂—Q₄—CH₂CH₂ Me O O 222 Me O O CH₂CH₂(N(COMe)CH₂CH₂)₂ Me O O 223 Me O O CH₂CH₂(N(COEt)CH₂CH₂)₂ Me O O 224 Me O O CH₂CH₂(N(COPh)CH₂CH₂)₂ Me O O 225 Me O O CH₂CH₂(N(COQ₃)CH₂CH₂)₂ Me O O 226 Me O O CH₂—CO—CH₂ Me O O 227 Me O O CH₂—CO—CH(CH)CH₂ Me O O 228 Me O O CH₂—CO—CH(O—COQ₃)CH₂ Me O O 229 Me O O CH₂—CO—CO—CH₂ Me O O 230 Me O O Q₅ Me O O 231 Me O O Q₆ Me O O 232 Me O O Q₇ Me O O 233 Me O O Q₈ Me O O 234 Me O O (CH₂)₂ Me O S 235 Me O O (CH₂)₃ Me O S 236 Me O O (CH₂)₄ Me O S 237 Me O O (CH₂)₅ Me O S 238 Me O O (CH₂)₆ Me O S 239 Me O O (CH₂)₇ Me O S 240 Me O O (CH₂)₈ Me O S 241 Me O O CH(Me)CH₂ Me O S 242 Me O O CH(Me)C(Me) Me O S 243 Me O O CH₂CH(O—COQ₃)CH₂ Me O S 244 Me O O CH₂CH(S—COQ₃)CH₂ Me O S 245 Me O O CH₂(S—COQ₃)CH(S—COQ₃)CH₂ Me O S 246 Me O O (CH₂)₂ Me O N—Me 247 Me O O (CH₂)₂ Me O N—Et 248 Me O O (CH₂)₂ Me O N—Pr-n 249 Me O O (CH₂)₂ Me O N—Pr-i 250 Me O O (CH₂)₂ Me O N—Bu-t 251 Me O O (CH₂)₂ Me O N—Ph 252 Me O O (CH₂)₂ Me O NCH₂Ph 253 Me O O (CH₂)₃ Me O NH 254 Me O O (CH₂)₄ Me O NH 255 Me O O (CH₂)₅ Me O NH 256 Me O O (CH₂)₆ Me O NH 257 Me O O (CH₂)₇ Me O NH 258 Me O O (CH₂)₈ Me O NH 259 Me O O CH₂CH(Me) Me O NH 260 Me O O CH₂CH(Et) Me O NH 261 Me O O CH₂CH(Ph) Me O NH 262 Me O O CH₂CH(CH₂Ph) Me O NH 263 Me O O CH₂C(Me)₂ Me O NH 264 Me O O CH(Ph)CH₂ Me O NH 265 Me O O CH(3-Q₃COOPh)CH₂ Me O NH 266 Me O O CH(4-Q₃COOPh)CH₂ Me O NH 267 Me O O CH(Ph)CH₂ Me O N—Me 268 Me O O CH(CH₂Ph)CH₂ Me O NH 269 Me O O CH(Ph)CH(Me) Me O NH 270 Me O O CH(Ph)CH(Me) Me O N—Me 271 Me O O CH(4-Q₃COOPh)CH(Me) Me O N—Me 272 Me O O Q₉ Me O — 273 Me O O Q₁₀ Me O — 274 Me O O 2,2,6,6-Me₄—Q₁₀ Me O — 275 Me O O CH₂—Q₁₁ Me O — 276 Me O O CH₂—Q₉ Me O — 277 Me O O CH₂—Q₁₀ Me O — 278 Me O O CH₂CH₂—Q₁₁ Me O — 279 Me O O CH₂CH₂—Q₉ Me O — 280 Me O O CH₂CH₂—Q₁₀ Me O — 281 Me O O 1-Ph-2 Me O NH 282 Me O O 1-Ph-3 Me O NH 283 Me O O 1-Ph-3 Me O NH 284 Me O O 1-(5-Cl—Ph)-2 Me O NH 285 Me O O 1-(4-Me—Ph)-2 Me O NH 286 Me O O 1-(4-t-Bu—Ph)-2 Me O NH 287 Me O O 1-(2-Me—Ph)-3 Me O NH 288 Me O O 1-(2,6-Cl₂—Ph)-4 Me O NH 289 Me O O 1-(4-Me—Ph)-3 Me O NH 290 Me O O 1-(5-O-COQ₃—Ph)-4 Me O NH 291 Me O O

Me O NH 292 Me O O

Me O NH 293 Me O O CH₂-1-(5-Me—Ph)-2 Me O NH 294 Me O S (CH₂)₂ Me O S 295 Me O S (CH₂)₃ Me O S 296 Me O S (CH₂)₄ Me O S 297 Me O S (CH₂)₅ Me O S 298 Me O S (CH₂)₆ Me O S 299 Me O S (CH₂)₇ Me O S 300 Me O S (CH₂)₈ Me O S 301 Me O S CH(Me)CH(Me) Me O S 302 Me O S CH₂CH₂SCH₂CH₂ Me O S 303 Me O S CH₂CH(COOEt) Me O NH 304 Me O S 1-Ph-2 Me O NH 305 Me O S 1-Ph-4 Me O NH 306 Me O NH (CH₂)₂ Me O NH 307 Me O NH (CH₂)₂ Me O N—Me 308 Me O NH (CH₂)₂ Me O N—Et 309 Me O NH (CH₂)₂ Me O N—Pr-n 310 Me O NH (CH₂)₂ Me D N—Pr-i 311 Me O NH (CH₂)₃ Me O NH 312 Me O NH (CH₂)₃ Me O N—Me 313 Me O NH (CH₂)₄ Me O N—Pr-n 314 Me O NH (CH₂)₅ Me O NH 315 Me O NH (CH₂)₆ Me O NH 316 Me O NH (CH₂)₇ Me O NH 317 Me O NH (CH₂)₈ Me O NH 318 Me O NH (CH₂)₉ Me O NH 319 Me O NH (CH₂)₁₀ Me O NH 320 Me O NH (CH₂)₁₁ Me O NH 321 Me O NH (CH₂)₁₂ Me O NH 322 Me O NH CH₂CH(Me) Me O NH 323 Me O NH CH₂C(Me)₂CH₂ Me O NH 324 Me O NH CH₂CH(COOEt) Me O NH 325 Me O NH CH₂CH₂CH(COOEt) Me O NH 326 Me O NH CH₂CH₂CH₂CH(COOEt) Me O NH 327 Me O NH CH₂CH₂CH₂CH₂CH(COOEt) Me O NH 328 Me O NH CH₂CH₂OCH₂CH₂ Me O NH 329 Me O NH CH₂CH₂OCH₂CH₂)₂ Me O NH 330 Me O NH CH₂CH₂(OCH₂CH₂)₃ Me O NH 331 Me O NH CH₂CH₂(OCH₂CH₂)₄ Me O NH 332 Me O NH CH₂CH₂N(Me)CH₂CH₂ Me O NH 333 Me O NH CH₂CH₂N(COQ₃)CH₂CH₂ Me O NH 334 Me O NH CH₂CH₂(N(COQ₃)CH₂CH₂)₂ Me O NH 335 Me O NH CH₂CH₂(N(COQ₃)CH₂CH₂)₃ Me O NH 336 Me O NH CH₂CH₂(N(COQ₃)CH₂CH₂)₄ Me O NH 337 Me O NH CH₂CH₂(N(COQ₃)CH₂CH₂)₅ Me O NH 338 Me O NH CH₂CH₂(N(COQ₃)CH₂CH₂)₆ Me O NH 339 Me O NH CH₂CH₂N(COQ₃)—(CH₂)₃ Me O NH 340 Me O NH CH₂CH₂N(Me)—(CH₂)₃ Me O NH 341 Me O NH (CH₂)₃N(COQ₃)—(CH₂)₃ Me O NH 342 Me O NH (CH₂)₄N(COQ₃)—(CH₂)₄ Me O NH 343 Me O NH (CH₂)₄(N(COQ₃)—(CH₂)₄)₂ Me O NH 344 Me O NH (CH₂)₄(N(COQ₃)—(CH₂)₄)₃ Me O NH 345 Me O NH (CH₂)₆N(COQ₃)—(CH₂)₆ Me O NH 346 Me O NH 1-cyclo-C₆H₁₀-2 Me O NH 347 Me O NH 1-cyclo-C₆H₁₀-5 Me O NH 348 Me O NH Q₁₀ Me O — 349 Me O NH CH₂CH₂Q₁₀ Me O — 350 Me O NH 1-Ph-2 Me O NH 351 Me O NH 1-Ph-3 Me O NH 352 Me O NH 1-Ph-4 Me O NH 353 Me O NH 1-(4-Cl—Ph)-2 Me O NH 354 Me O NH 1-(4,5-Me₂—Ph)-2 Me O NH 355 Me O NH 1-(4-OMe—Ph)-2 Me O NH 356 Me O NH 1-(2-Me—Ph)-3 Me O NH 357 Me O NH 1-(4-Me—Ph)-3 Me O NH 358 Me O NH. 1-(4-OMe—Ph)-3 Me O NH 359 Me O NH 1-(2-Cl—Ph)-4 Me O NH 360 Me O NH 1-(2,5-Cl₂—Ph)-4 Me O NH 361 Me O NH 1-(2,6-Cl₂—Ph)-4 Me O NH 362 Me O NH 1-(2-OMe—Ph)-4 Me O NH 363 Me O NH 1-(1,3,5,6-Me₄—Ph)-4 Me O NH 364 Me O N—Me (CH₂)₂ Me O N—Me 365 Me O N—Et (CH₂)₂ Me O N—Et 366 Me O N—Pr-n (CH₂)₂ Me O N—Pr 367 Me O N—Pr-i (CH₂)₂ Me O N—Pr 368 Me O — Q₄ Me O — 369 Me O — Q₁₂ Me O — 370 Me O — Q₁₃ Me O — 371 Me O — Q₁₄ Me O — 372 Et O O (CH₂)₂ Et O O 373 Pr-i O O (CH₂)₂ Pr-i O O 374 CH₂Cl O O (CH₂)₂ CH₂Cl O O 375 CF₃ O O (CH₂)₂ CF₃ O O 376 Ph O O (CH₂)₂ Ph O O 377 2-Cl—Ph O O (CH₂)₂ 2-Cl—Ph O O 378 3-Cl—Ph O O (CH₂)₂ 3-Cl—Ph O O 379 4-Cl—Ph O O (CH₂)₂ 4-Cl—Ph O O 380 2-Me—Ph O O (CH₂)₂ 2-Me—Ph O O 381 3-Me—Ph O O (CH₂)₂ 3-Me—Ph O O 382 4-Me—Ph O O (CH₂)₂ 4-Me—Ph O O 383 4-t-Bu—Ph O O (CH₂)₂ 4-t-Bu—Ph O O 384 2-CF₃—Ph O O (CH₂)₂ 2-CF₃—Ph O O 385 4-CF₃—Ph O O (CH₂)₂ 4-CF₃—Ph O O 386 2,4-Me₂—Ph O O (CH₂)₂ 2,4-Me₂—Ph O O 387 3,4-Me₂—Ph O O (CH₂)₂ 3,4-Me₂—Ph O O 388 4-CH—Ph O O (CH₂)₂ 4-OH—Ph O O 389 4-MeO—Ph O O (CH₂)₂ 4-MeO—Ph O O 390 4-CF₃O—Ph O O (CH₂)₂ 4-CF₃O—Ph O O 391 4-PhO—Ph O O (CH₂)₂ 4-PhO—Ph O O 392 2,4-(MeO)₂—Ph O O (CH₂)₂ 2,4-(MeO)₂—Ph O O 393 3,4-(MeO)₂—Ph O O (CH₂)₂ 3,4-(MeO)₂—Ph O O 394 4-COOMe—Ph O O (CH₂)₂ 4-COOMe—Ph O O 395 2,4-Cl₂—Ph O O (CH₂)₂ 2,4-Cl₂—Ph O O 396 3,4-Cl₂—Ph O O (CH₂)₂ 3,4-Cl₂—Ph O O 397 Q₁₅ O O (CH₂)₂ Q₁₅ O O 398 Q₁₆ O O (CH₂)₂ Q₁₆ O O 399 Q₁₇ O O (CH₂)₂ Q₁₇ O O 400 Q₁₈ O O (CH₂)₂ Q₁₈ O O 401 Q₁₉ O O (CH₂)₂ Q₁₉ O O 402 6-Cl—Q₁₉ O O (CH₂)₂ 6-Cl—Q₁₉ O O 403 Me S NH (CH₂)₂ Me S NH 404 Me S NH (CH₂)₃ Me S NH 405 Me S NH (CH₂)₄ Me S NH 406 Me S NH 1-Ph-2 Me S NH 407 Me S NH 1-Ph-3 Me S NH 408 Me S NH 1-Ph-4 Me S NH

Table 1 shows that, for example, R of compound No. 141 is “1-cyclo-C₅H₈-2” which means Y¹ and Y² are linked to the 1-position and 2-potition, respectively, of a cyclopentyl ring. It is similarly shown that R of compound No. 154 is “1-Ph-2” which means Y¹ and Y² are linked to the 1-position and 2-position, respectively, of the phenyl ring of 1,2-phenylene group.

Table 2 lists characteristic properties of the typical compounds shown in Table 1.

TABLE 2 Compound No. Property 2 m.p. 54° C. 4 m.p. 91° C. 21 Paste [NMR (CDCl₃/TMS, δ value (ppm))] 1.47(d, 6.6Hz, 3H), 2.94(s, 6H), 4.40(dd, 6.7Hz, 12.1Hz, 1H), 4.60(dd, 3.2Hz, 12.1Hz, 1H), 5.4-5.6(m, 1H) 35 nD 1.5722 (22° C.) 82 nD 1.5403 (22° C.) 95 m.p. 95° C. 96 m.p. 190° C. 106 Paste [NMR (CDCl₃/TMS, δ value (ppm))] 2.97(s, 9H), 4.60(dd, 2H), 4.75(dd, 2H), 5.65-5.80(m, 1H). 140 m.p. 79° C. 156 m.p. 205° C. 166 m.p. 184° C. 176 m.p. 149° C. 184 m.p. 122° C. 187 nD 1.5416 (26° C.) 188 nD 1.5325 (26° C.) 196 nD 1.5222 (26° C.) 197 Paste [NMR (CDCl₃/TMS, δ value (ppm))] 2.95(s, 6H), 3.50-3.70(m, ≈24H), 3.76-3.82(m, 4H), 4.45-4.52(m, 4H). 198 Paste [NMR (CDCl₃/TMS, δ value (ppm))] 2.97(s, 6H), 3.57-3.75(m, ≈38H), 3.76-3.83(m, 4H), 4.45-4.53(m, 4H). 214 nD 1.5627 (21° C.) 219 Paste [NMR (CDCl₃/TMS, δ value (ppm))] 2.92(s, 69H), 2.96-3.06(m, 6H), 4.34-4.45(m, 6H). 281 m.p. 112° C. 282 m.p. 152° C. 283 m.p. 167° C. 288 m.p. 164° C. 306 m.p. 149° C. 350 m.p. 189° C. 351 m.p. 210° C. 352 m.p. 260° C.

The bis-thiadiazole derivatives of the general formula (I) or salts thereof according to the present invention are useful for agricultural and horticultural disease control. For example, these compounds have a very high controlling effect against various diseases, for instance, rice blast (Pyricularia oryzae), rice sheath blight (Rhizoctonia solani), rice helminthosporium leaf spot (Cochiobolus miyabeanus), powdery mildew of various host plants such as powdery mildew of barley and wheat (Erysiphe graminis), oats crown rust (Puccinia coronata) and rust of other plants, tomato late blight (Phytophthora infestans) and late blight or Phytophthora rots of other plants, downy mildew of various plants such as cucumber downy mildew (Pseudoperonospora cubensis) and grape downy mildew (Plasmopara viticola), apple scab (Venturia inaequalis), apple alternaria leaf spot (Alternaria mali), pear black spot (Alternaria kikuchiana), citrus melanose (Diaporthe citri), bacterial diseases including Pseudomonas diseases such as cucumber bacterial blight (Pseudomonas syringae pv. lachrymans) and tomato bacterial wilt (Pseudomonas solanacearum), Xanthomonas diseases such as cabbage black rot (Xanthomonas campestris), rice bacterial leaf blight (Xanthomonas oryzae) and citrus canker (Xanthomonas citri) and Erwinia diseases such as cabbage bacterial soft rot (Erwinia carotovora), and viral diseases such as tobacco mosaic (Tobacco mosaic virus).

The agrohorticultural disease controller containing the bis-thiadiazole derivative of general formula (I) or salts thereof as an active ingredient according to the present invention exhibits a marked controlling effect against the above-exemplified diseases which damage paddy field crops, upland field crops, fruit trees, vegetables, other crop plants, flowers, ornamental plants, and the like. Accordingly, the desired effects of the agrohorticultural disease controller of the present invention can be obtained by applying the disease controller to the paddy field water, stalks and leaves or soil of the paddy field, upland field, fruit trees, vegetables, other crops, flowers and ornamental plants at a season at which the diseases are expected to occur, before their occurrence or at the time when their occurrence has been confirmed.

The agrohorticultural disease controller of the present invention is generally put to use after being prepared into a conveniently usable form according to an ordinary manner for preparation of pesticides.

That is, the bis-thiadiazole derivative represented by the general formula (I) or a salt thereof according to the present invention and, optionally, an adjuvant are blended with an appropriate inert carrier in a proper proportion, prepared into a suitable preparation form such as suspension, emulsifiable concentrate, soluble concentrate, wettable powder, granule, dust, tablet, etc. and put to use through dissolution, separation, suspension, mixing, impregnation, adsorption or sticking.

The inert carrier used in the present invention may be either solid or liquid. As the material usable as solid carrier, there can be exemplified soybean flour, cereal flour, wood flour, bark flour, saw dust, powdered tobacco stalks, powdered walnut shells, bran, powdered cellulose, extraction residue of vegetables, powdered synthetic polymers of synthetic resins and the like, clays such as kaolin, bentonite, acid clay and the like, talcs such as talc, pyrophyllite and the like, silica powders and flakes such as diatomaceous earth, siliceous sand, mica, white carbon (namely, synthetic, high-dispersion silicic acid, also called finely divided hydrated silica or hydrated silicic acid, some of the commercially available products thereof contain calcium silicate as the major component), activated carbon, powdered sulfur, pumice, calcined diatomaceous earth, crushed brick, fly ash, sand, inorganic mineral powders such as calcium carbonate, calcium phosphate and the like, chemical fertilizers such as ammonium sulfate, ammonium phosphate, ammonium nitrate, urea, ammonium chloride and the like, and compost. These carriers may be used alone or as a mixture thereof.

The material constituting the liquid carrier is selected from materials having a dissolving ability in themselves and materials which have no dissolving ability in themselves but can disperse the active ingredient compound by aid of an adjuvant. The following are typical examples of the liquid carrier material, which can be used either alone or in the form of a mixture: water; alcohols such as methanol, ethanol, isopropanol, butanol, ethylene glycol and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, diisobutyl ketone, cyclohexanone and the like; ethers such as ethyl ether, dioxane, cellosolve, dipropyl ether, tetrahydrofuran and the like; aliphatic hydrocarbons such as kerosene, mineral oils and the like; aromatic hydrocarbons such as benzene, toluene, xylene, solvent naphtha, alkylnaphthalene and the like; halogenated hydrocarbons such as dichloroethene, chloroform, carbon tetrachloride, chlorobenzene and the like; esters such as ethyl acetate, diisopropyl phthalate, dibutyl phthalate, dioctyl phthalate and the like; amides such as dimethylformamide, diethylformamide, dimethylacetamide and the like; nitriles such as acetonitrile and the like; dimethyl sulfoxide; etc.

As the adjuvant, the following can be referred to as typical ones. These adjuvants are used depending upon purposes, either alone or in combination of two or more in some cases. It is also possible to use no adjuvant at all, in some cases.

A surfactant is used for the purpose of emulsifying, dispersing, solubilizing and/or wetting an active ingredient. As the surfactant, there can be exemplified polyoxyethylene alkyl ethers, polyoxyethylene alkylaryl ethers, polyoxyethylene higher fatty acid esters, polyoxyethylene resin acid esters, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, alkylarylsulfonates, naphthalenesulfonic acid condensates, ligninsulfonic acid salts, higher alcohol sulfuric esters, etc.

The following adjuvants can also be used for the purpose of stabilizing, tackifying and/or binding the dispersion of active ingredient compound: casein, gelatin, starch, methyl cellulose, carboxymethyl cellulose, gum arabic, polyvinyl alcohol, turpentine, bran oil, bentonite, ligninsulfonic acid salts and the like.

Further, wax, stearic acid salts, alkyl phosphates and the like may be used as an adjuvant for the purpose of improving flowability of a solid product.

Further, naphthalenesulfonic acid condensates, polycondensed phosphoric acid salts and the like may also be used as a peptizer for dispersible products.

Adjuvants such as silicone oils may also be used as a defoaming agent.

The content of the active ingredient may be increased or decreased according to the need. For example, in dusts and granules, the suitable content thereof is from 0.01 to 50% by weight. In emulsifiable concentrates and wettable powders, too, the suitable content thereof is from 0.01 to 50% by weight.

For controlling various diseases, the agrohorticultural disease controller of the present invention itself or its appropriate dilution or suspension in water or the like is applied to a crop on which the diseases are expected to occur or a site where occurrence of the diseases is undesirable, in an amount effective for disease control. For example, for controlling the diseases of paddy rice, said disease controller can be used by a method such as direct application to regular paddy field, application to a rice nursery bed, dressing of seeds for direct sowing to flooded paddy field, seed disinfection, etc. For controlling the diseases of barley, wheat, oat or the like, the disease controller of the present invention is applied to stalks and leaves or used for soil treatment where the disease controller is absorbed from the roots.

The application amount of the agrohorticultural disease controller of the present invention may vary depending on various factors including purpose of application, objective disease, state of plant growth, tendency of prevalence of the disease, weather, environmental conditions, preparation form, method of application, site of application, time of application, etc. The application amount, however, should be properly chosen in the range of from 0.1 g to 10 kg per 10 ares as expressed in terms of amount of active ingredient, depending on purposes.

In order to expand the spectrum of controllable diseases and the time period of effective application or to reduce the dosage, it is also possible to use the disease controller of the present invention in the form of a mixture with other agrohorticultural disease controllers.

Next, typical examples, formulation examples and test examples of the present invention are presented below. The present invention is by no means limited by these examples.

EXAMPLE 1 Production of ethylene-bis(4-methyl-1,2,3-thiadiazole-5-carboxylate) (Compound No. 2)

In 30 ml of tetrahydrofuran was dissolved 0.80 g (4.9 mmol) of 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride, to which was then added 0.12 g (2.0 mmol) of ethylene glycol. While stirring the mixture at room temperature, 0.50 ml of triethylamine was dropwise added thereto and stirred at room temperature for 4 hours. After the reaction was completed, ethyl acetate was added to the reaction mixture, the organic layer was washed successively with aqueous solution of hydrochloric acid and aqueous solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 2:1 mixture of n-hexane and ethyl acetate. Thus, the objective compound was obtained in a yield of 0.34 g.

Property: m.p. 54° C.

Yield: 56%

EXAMPLE 2 Production of 2-butynylene-bis(4-methyl-1,2,3-thiadiazole-5-carboxylate) (Compound No. 140)

In 30 ml of tetrahydrofuran was dissolved 0.70 g (4.3 mmol) of 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride, to which was added 0.15 g (1.7 mmol) of 2-butyne-1,4-diol. While stirring the mixture at room temperature, 0.50 ml of triethylamine was dropwise added and stirred at room temperature for 4 hours. After the reaction was completed, ethyl acetate was added to the reaction mixture, the organic layer was washed successively with aqueous solution of hydrochloric acid and aqueous solution of sodium hydrogen carbonate and dried on anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 2:1 mixture of n-hexane and ethyl acetate. Thus, the objective compound was obtained in a yield of 0.34 g.

Property: m.p. 79° C.

Yield: 61%

EXAMPLE 3 Production of p-phenylene-bis(4-methyl-1,2,3-thiadiazole-5-carboxylate) (Compound No. 156)

In 30 ml of tetrahydrofuran was dissolved 1.0 g (6.2 mmol) of 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride, to which was then added 0.27 g (2.5 mmol) of p-hydroquinone. While stirring the mixture at room temperature, 0.50 ml of triethylamine was dropwise added thereto and stirred at room temperature for 4 hours. After the reaction was completed, ethyl acetate was added to the reaction mixture, and the organic layer was washed successively with aqueous solution of hydrochloric acid and aqueous solution of sodium hydrogen carbonate and dried on anhydrous magnesium sulfate. The dried organic solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using 2:1 mixture of n-hexane and ethyl acetate. Thus, the objective compound was obtained in a yield of 0.30 g.

Property: m.p. 205° C.

Yield: 34%

EXAMPLE 4 Production of p-α,α-xylylene-bis(4-methyl-1,2,3-thiadiazole-5-carboxylate (Compound No. 184)

In 30 ml of acetonitrile was dissolved 0.50 g (3.5 mmol) of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid, to which were added 0.37 g (1.4 mmol) of p-α,α-xylylene dibromide and 0.50 g (3.6 mmol) of anhydrous potassium carbonate. The resulting mixture was heated under reflux for 4 hours. After the reaction was completed, ethyl acetate was added to the reaction mixture, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using 4:1 mixture of n-hexane and ethyl acetate. Thus, the objective compound was obtained in a yield of 0.15 g.

Property: m.p. 122° C.

Yield: 27%

EXAMPLE 5 Production of polyoxyethylene (mean value of n=4)-bis(4-methyl-1,2,3-thiadiazole-5-carboxylate) (Compound No. 196)

In 30 ml of tetrahydrofuran was dissolved 1.60 g (10 mmol) of 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride, to which was added 0.50 g (2.5 mmol) of PEG 200 (polyethylene glycol). While stirring the resulting mixture at room temperature, 0.50 ml of triethylamine was dropwise added thereto and stirred at room temperature for 4 hours. After the reaction was completed, ethyl acetate was added to the reaction mixture, the organic layer was washed successively with aqueous solution of hydrochloric acid and aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using 1:1 mixture of n-hexane and ethyl acetate. Thus, the objective compound was obtained in a yield of 0.59 g.

Property: nD 1.5222 (26° C.)

Yield: 52%

EXAMPLE 6 Production of 2,6-dichloro-4-(4-methyl-1,2,3-thiadiazol-5-ylcarbonylamino)-phenyl 4-methyl-1,2,3-thiadiazole-5-carboxylate (Compound No. 288)

In 30 ml of tetrahydrofuran was dissolved 1.0 g (4.1 mmol) of 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride, to which was added 0.20 g (2.0 mmol) of 2,6-dichloro-p-aminophenol. While stirring the mixture at room temperature, 1.0 ml of triethylamine was dropwise added and stirred at room temperature for 4 hours. After the reaction was completed, ethyl acetate was added to the reaction mixture, and the organic layer was washed successively with aqueous solution of hydrochloric acid and aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Thus, the objective compound was obtained in a yield of 0.62 g.

Property: m.p. 260° C.

Yield: 33%

EXAMPLE 7 Production of N,N′-p-phenylenebis(4-methyl-1,2,3-thiadiazole-5-carboxamide) (Compound No. 352)

In 30 ml of tetrahydrofuran was dissolved 0.80 g (4.9 mmol) of 4-methyl-1,2,3-thiadiazole-5-carbonyl chloride, to which was added 0.20 g (1.9 mmol) of p-phenylenediamine. While stirring the mixture at room temperature, 1.0 ml of triethylamine was dropwise added and stirred at room temperature for 4 hours. After the reaction was completed, ethyl acetate was added to the reaction mixture, and the organic layer was washed successively with aqueous solution of hydrochloric acid and aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Thus, the objective compound was obtained in a yield of 0.62 g.

Property: m.p. 164° C.

Yield: 73%

Next, typical examples and test examples of the present invention are presented below.

In the formulation examples, the term parts means parts by weight.

Formulation Example 1

The compound of Table 1 50 parts Xylene 40 parts Mixture of polyoxyethylene 10 parts nonylphenyl ether and calcium alkylbenzenesulfonate

The ingredients mentioned above are uniformly mixed and dissolved together to prepare an emulsifiable concentrate.

Formulation Example 2

The compound of Table 1 3 parts Clay powder 82 parts Diatomaceous earth powder 15 parts

The ingredients mentioned above are uniformly mixed and pulverized to prepare a dust.

Formulation Example 3

The compound of Table 1 5 parts Powdered mixture of bentonite 90 parts and clay Calcium ligninsulfonate 5 parts

The ingredients mentioned above are uniformly mixed together, kneaded together with an appropriate quantity of water, granulated and dried to prepare a granular composition.

Formulation Example 4

The compound of Table 1 20 parts Kaolinite and synthetic 75 parts high-disperse silicic acid Mixture of polyoxyethylene 5 parts nonylphenyl ether and calcium alkylbenzenesulfonate

The ingredients mentioned above are uniformly mixed and pulverized to prepare a wettable powder.

Test Example 1 Rice Blast-controlling Test by Submerged Application

A chemical agent containing the compound shown in Table 1 as an active ingredient was applied to paddy rice plants of the 5- to 6-leaved stage, cultivated in {fraction (1/10000)} are pots, by the method of submerged application at a dosage of 200 g/10 a as expressed in terms of active ingredient. After standing in a greenhouse for a week, the plants were inoculated with a spore suspension of rice blast fungus (Pyricularia oryzae) by the method of spraying.

After the inoculation, the plants were allowed to stand in a moist chamber for one day and then in a greenhouse for 6 days to cause the disease sufficiently. Then, lesions on each leaf were counted and compared with those in the untreated plot, from which the controlling degree was calculated, whereby the effect was judged according to the following criterion:

Effect Controlling degree (%) A 100-95  B 94-85 C 84-60 D 59-0 

The results of the above test demonstrate that the compounds listed in Table 1 were found to have a marked blast-controlling activity. Of these compounds, the following were rated C or higher: Compound Nos. 2, 82, 96, 106, 140, 156, 166, 176, 187, 188, 196, 219, 281, 282, 283, 288, 351 and 352; among which Compound Nos. 2, 106, 156, 166, 188, 196, 219, 282, 283, 288, 351 and 352 exhibit so high a controlling effect as rated A. 

What is claimed is:
 1. A bis-thiadiazole derivative represented by the following general formula (I) or a salt thereof:

wherein R¹ and R², same or different, represent hydrogen atom, C₁-C₈ alkyl group, halo C₁-C₄ alkyl group, phenyl group, substituted phenyl group having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, 5- or 6 -membered hererocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, or substituted 5- or 6 membered heterocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom and having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups; X¹ and X², same or different, represent oxygen atom or sulfur atom; Y¹ and Y², same or different, represent oxygen atom, sulfur atom or —N(R³)— in which R³ is as defined later; and R represents C₀-C₃₀ alkylene group, an alkylene group of the following formula:

in which R³ and R⁴, same or different, represent hydrogen atom, halogen atom, hydroxyl group, nitro group, cyano group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, C₁-C₄ alkylsulfinyl group, C₁-C₄ alkylsulfonyl group, hydroxy C₁-C₄ alkyl group, C₁-C₄ alkoxy C₁-C₄ alkyl group, C₁-C₄ alkoxycarbonyl group, amino group, substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl group, phenyl group and substituted phenyl groups having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, amino C₁-C₄ alkyl group, substituted amino C₁-C₄ alkyl group having 1 or 2 same or different substituents selected from substituted phenyl groups having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, phenyl group, substituted phenyl group having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, phenyl C₁-C₄ alkyl group, substituted phenyl C₁-C₄ alkyl group having, on the ring thereof, 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, phenoxy group, substituted phenoxy group having, on the ring thereof, 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, phenoxy C₁-C₄ alkyl group, substituted phenoxy C₁-C₄ alkyl group having, on the ring thereof, 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, 5- or 6-membered heterocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, substituted 5 or 6-membered heterocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom and having 1 to 4 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, 5- or 6-membered heterocycle C₁-C₄ alkyl group containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, substituted 5- or 6-membered hetero cycle C₁-C₄ alkyl group containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom and having 1 to 4 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, or a group of

(wherein R⁶ represents C₁-C₆ alkylene group, substituted C₁-C₆ alkylene group substituted by one or more same or different halogen atoms or C₁-C₄ alkyl groups, or C₁-C₆ alkylene group which may be intercepted by —O—, —S(O)_(n)— in which n is an integer of 0-2, or —N(R⁸)— in which R⁸ represents hydrogen atom, halogen atom, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxycarbonyl group, phenyl group, substituted phenyl group having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, phenyl C₁-C₄ alkyl group, substituted phenyl C₁-C₄ alkyl group having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, or

(wherein R¹¹ represents C₁-C₆ alkylene group or substituted C₁-C₆ alkylene group having one or more substituents selected from the group consisting of halogen atom and C₁-C₄ alkyl group; R¹² represents hydrogen atom, C₁-C₈ alkyl group, halo C₁-C₄ alkyl group, phenyl group, substituted phenyl group having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, 5- or 6-membered heterocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, or substituted 5- or 6-membered heterocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom and having 1 to 4 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups; Y⁴ represents —O—, —S— or —N(R¹³)— in which R¹³ represents hydrogen atom or C₁-C₄ alkyl group; X⁴ represents oxygen atom or sulfur atom; q represents an integer of 0 to 1; and r represents an integer of 0 to 1); R⁷ represents hydrogen atom, C₁-C₈ alkyl group, halo C₁-C₈ alkyl group, phenyl group, substituted phenyl group having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, phenyl C₁-C₄ alkyl group, substituted phenyl C₁-C₄ alkyl group having, on the ring thereof, 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, 5- or 6-membered heterocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, or substituted 5 or 6-membered heterocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom and having, on the ring thereof, 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups; Y³ represents —O—, —S— or —N(R⁸)— in which R⁸ is as defined above; X³ represents oxygen atom or sulfur atom; m represents an integer of 0 to 5; and p represents an integer of 0 or 1); and letter a represents an integer of 1 to 30; further, R³ and R⁴ may be taken conjointly to form a 3- to 8-membered ring including a C₀-C₇ alkylene group, and said 3- to 8-membered ring may be intercepted by —O—, —S(O)_(n)— in which n represents an integer of 0-2, —N(R⁸)— in which R⁸ is as defined above, or —C(R⁹)(R¹⁰)— in which R⁹ and R¹⁰, same or different, represent halogen atom, C₁-C₄ alkyl group or a group of the following formula:

in which R¹¹, R¹², X⁴, Y⁴, q and r are as defined above; and R⁹ and R¹⁰ may be taken conjointly to form a 3- to 7-membered ring including a C₂-C₆ alkylene group; and R alternatively represents C₀-C₃₀ alkylene group which may be intercepted by one or more same or different group selected from the group consisting of —O—, —S(O)_(n)— in which n is as defined above, —N(R³)— in which R³ is as defined above, —C(R³)═C(R⁴)— in which R³ and R⁴ are as defined above,

(Z represents hydrogen atom, dichloro group, dimethyl group, trimethyl group, tetramethyl group, halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group, substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, or a group of the following formula:

in which R⁶, R⁷, Y³, X³, m and p are as defined above) and

(Z is as defined above) provided that: (1) when R¹ is defined as above, each of X¹ and X² is oxygen atom, Y¹ is oxygen atom or sulfur atom, Y² is NR³ (wherein R³ is defined as R³ above), and R is C₁-C₆ alkylene group or

(wherein R³ and R⁴ represent hydrogen atom and letter a represents an integer of 1 to 6, or R³ and R⁴, same or different, represent C₁-C₆ alkyl group or phenyl group, and a is defined as above), then R² is not hydrogen atom, halogen atom or C₁-C₆ alkyl group; (2) when R¹ is defined as above, each of X¹ and X² is oxygen atom, Y¹ is oxygen atom or sulfur atom, Y² is oxygen atom, and R is C₁-C₁₂ alkylene group or

(wherein R³ and R⁴ represent hydrogen atom and letter a represents an integer of 1 to 12, or each of R³ and R⁴ is hydroxyl group, and a is defined as above), then R² is not hydrogen atom, halogen atom or C₁-C₆ alkyl group; (3) when R¹ is defined as above, each of X¹ and X² is oxygen atom, Y¹ is NR³ (wherein R³ is defined as above), Y² is oxygen atom or —NH—, and R is

(wherein Z is hydrogen atom ), then R² is not hydrogen atom, halogen atom, or C₁-C₆ alkyl group; and (4) when R¹ is the same as defined above, each of X¹ and X² is oxygen atom, Y¹ is NR³ (wherein R³ is the same as defined above), Y² is —NH—, and R is C₁-C₁₂, alkylene group, or

wherein R³ and R⁴ represent hydrogen atom and letter a represents an integer of 1 to 12, then R² is not hydrogen atom, or halogen atom, C₁-C₆ alkyl group.
 2. A bis-thiadiazole derivative or a salt thereof according to claim 1, wherein R¹ and R², same or different, represent hydrogen atom, C₁-C₈ alkyl group or halo C₁-C₄ alkyl group; X¹ and X², same or different, represent oxygen atom or sulfur atom; Y¹ and Y², same or different, represent oxygen atom, sulfur atom or —N(R³)— in which R³ is as defined later; and R represents C₀-C₃₀ alkylene group, an alkylene group represented by the following formula:

in which R³ and R⁴, same or different, represent hydrogen atom, halogen atom, nitro group, cyano group, C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, C₁-C₄ alkoxycarbonyl group, phenyl group, substituted phenyl group having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, or a group of the following formula:

(wherein R⁶ represents C₁-C₆ alkylene group, substituted C₁-C₆ alkylene group substituted by C₁-C₄ alkyl group, or C₁-C₆ alkylene group which may be intercepted by —O— or —S(O)_(n)— in which n is an integer of 0-2; R⁷ represents hydrogen atom, C₁-C₈ alkyl group, halo C₁-C₈ alkyl group, phenyl group, substituted phenyl group having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, 5- or 6-membered heterocycle containing 1 to 3 hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, substituted 5- or 6-membered heterocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom and having, on the ring thereof, 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups; Y³ represents —O—, —S— or —N(R⁸)— in which R⁸ represents hydrogen atom, halogen atom, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxycarbonyl group, phenyl group, substituted phenyl group having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, phenyl C₁-C₄ alkyl group, substituted phenyl C₁-C₄ alkyl group having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, or a group of the following formula:

(wherein R¹¹ represents C₁-C₆ alkylene group or substituted C₁-C₆ alkylene group having one or more same or different substituents selected from the group consisting of halogen atom and C₁-C₄ alkyl group; R represents hydrogen atom, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, phenyl group, substituted phenyl group having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, 5- or 6-membered heterocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, or substituted 5- or 6-membered heterocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom and having 1 to 4 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups; Y⁴ represents —O—, —S— or —N(R¹³)— in which R¹³ represents hydrogen atom or C₁-C₄ alkyl group; X⁴ represents oxygen atom or sulfur atom; q represents an integer of 0 to 2; and r represents an integer of 0 to 1); and X³ represents oxygen atom or sulfur atom; m, same or different, represents an integer of 0 to 10; and p represents an integer of 0 or 1); and letter a represents an integer of 1 to 30; further R³ and R⁴ may be taken conjointly to form a 3- to 8-membered ring including a C₀-C₇ alkylene group, and said 3- to 8-membered ring may be intercepted by —O—, —S(O)_(n)— in which n is an integer of 0 to 2, or —N(R⁸)— in which R⁸ is as defined above, or a C₀-C₃₀ alkylene group which may be intercepted by one or more same or different groups selected from the group consisting of —O—, —S(O)_(n)— in which n is as defined above, —N(R³)— in which R³ is as defined above, —(R³)═C(R⁴)— in which R³ and R⁴ are as defined above, —C≡C—, and a group of the following formula:

(Z represents halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group, substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, or a group of the following formula:

in which R⁶, R⁷, Y³, X³, m and p are as defined above).
 3. A bis-thiazole derivative or a salt thereof according to claim 2, wherein R¹ and R², same or different, represent hydrogen atom, C₁-C₈ alkyl group or halo C₁-C₄ alkyl group; X¹ and X², same or different, represent oxygen atom or sulfur atom; Y¹ and Y², same or different, represent oxygen atom, sulfur atom or —N(R³)— in which R³ is as defined later; and R represents C₀-C₃₀ alkylene group, an alkylene group represented by the following formula:

in which R³ and R⁴, same or different, represent hydrogen atom, halogen atom, nitro group, cyano group, C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, C₁-C₄ alkoxycarbonyl group, phenyl group or a group of the following formula:

(wherein R⁶ represents C₁-C₆ alkylene group, substituted C₁-C₆ alkylene group substituted by C₁-C₄ alkyl group, or C₁-C₆ alkylene group intercepted by —O— or —S(O)_(n) in which n is an integer of 0-2; R⁷ represents hydrogen atom, C₁-C₈ alkyl group, halo C₁-C₈ alkyl group, phenyl group, substituted phenyl group having 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups, 5- or 6-membered heterocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, or substituted 5- or 6-membered heterocycle containing 1 to 3 same or different hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom and having, on the ring thereof, 1 to 5 same or different substituents selected from the group consisting of halogen atom, nitro group, cyano group, hydroxyl group, mercapto group, C₁-C₄ alkyl group, halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group, amino group and substituted amino group having 1 or 2 same or different substituents selected from the group consisting of C₁-C₄ alkyl and phenyl groups; Y³ represents —O— or —S—; X³ represents oxygen atom or sulfur atom; m, same or different, represents an integer of 0 to 10; and p represents an integer of 0 or 1); and letter a represents an integer of 1 to 30; and R alternatively represents a C₀-C₃₀ alkylene group which may be intercepted by one or more same or different groups selected from the group consisting of —O—, —S(O)_(n)— in which n is as defined above, —N(R³)— in which R³ is as defined above, —C(R³)═C(R⁴)— in which R³ and R⁴ are as defined above, —C≡C— or a group of the following formula:

(Z is halogen atom, nitro group, cyano group, C₁-C₄ alkyl groups halo C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halo C₁-C₄ alkoxy group, C₁-C₄ alkylthio group, halo C₁-C₄ alkylthio group or a group of the following formula:

in which R⁶, R⁷, Y³, X³, m and p are as defined above).
 4. An agrohorticultural disease controller which comprises the bis-thiadiazole derivative or a salt thereof according to any one of claims 1 to 3 as an active ingredient.
 5. A method for controlling a plant disease which comprises treating a plant on which occurrence of plant disease is undesirable with an effective quantity of the agrohorticultural disease controller according to claim
 4. 